When available and used optimally, antiretroviral therapy (ART) can dramatically reduce the morbidity and mortality associated with perinatally-acquired HIV disease. In resource-limited settings such as South Africa, however, the most effective diagnostic tests and ART regimens for the management of perinatal HIV infection are often not available. As a result, more than 60,000 perinatal infections and 20,000 pediatric HIV deaths may occur annually in South Africa alone. Clinicians and policy-makers in South Africa currently select diagnostic tests and ART regimens for children based on limited available data about efficacy, toxicity, and cost. Decision analysis can complement more traditional clinical research methods by synthesizing data from multiple sources and projecting the future outcomes of diagnostic and therapeutic strategies over the lifetimes of HIV-infected children. This K01 Award application proposes three Specific Aims based on these methods: 1. To construct a Monte Carlo simulation model of perinatal HIV disease, and to use as parameters in the model the best available data in the literature and from collaborating investigators in South Africa. 2. To evaluate the long-term clinical outcomes and cost-effectiveness of ART initiation in the first year of life, compared to deferred therapy. 3. To evaluate the clinical outcomes and relative cost-effectiveness of currently recommended diagnostic testing algorithms for early infant diagnosis. To facilitate this proposed research, the Candidate, Andrea Ciaranello, MD, will pursue coursework in advanced biostatistics and modeling methodology, operations research, and ethical principles pertinent to HIV/AIDS in resource-limited settings. Dr. Ciaranello will benefit from the resources of the Massachusetts General Hospital and the Harvard School of Public Health; from the support of mentors with expertise in modeling techniques, perinatal HIV infection, and international HIV research and with outstanding records of mentorship; and from her collaborations with clinical investigators in South Africa and with the international Kids' ART-LINC research consortium. This K01 Award will facilitate Dr. Ciaranello's career development and her transition to an independent HIV clinical outcomes investigator. RELEVANCE (See instructions): This K01 Award will lead to analyses that will inform clinical decisions, as well as national and international policy guidelines, regarding the management of HIV infection in children. The proposed research aligns with the published priorities of the NIH Office of AIDS research, including the evaluation of the most effective, setting-specific strategies for diagnosis, care and treatment of HIV-infected children and adolescents.